A highly potent and selective inhibitor Roxyl-WL targeting IDO1 promotes immune response against melanoma

Journal of Enzyme Inhibition and Medicinal Chemistry

Xin Wang¹  Guangwei Xu¹  Tianqi Wang¹  Yongtao Li¹  Zhi Huang¹  Yan Fan²  Rong Xiang²  Jianyu Zheng³  Shengyong Yang⁴ 

[1] Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin, China;Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin, China;State Key Laboratory of Medicinal Chemical Biology, Tianjin, China;2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, Tianjin, Chin;State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin, China;State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China;

关键词: IDO1;    inhibitor;    melanoma;    immunotherapy;   

DOI  :  10.1080/14756366.2018.1471688

来源: publisher

【 摘 要 】

Indoleamine 2,3-dioxygenase 1 (IDO1) activity links to immune escape of cancers. Inhibition of IDO1 provides a new approach for cancer treatment. Most clinical IDO1 drugs show marginal efficacy as single agents. On basis of molecular docking and pharmacophore modelling, a novel inhibitor Roxyl-WL was discovered with a half maximal inhibitory concentration (IC50) value of 1 nM against IDO1 and 10–100-fold increased potent activity compared with IDO1 drugs in clinical trials. Roxyl-WL displayed excellent kinase spectrum selectivity with no activity out of the 337 protein kinases. In vitro, Roxyl-WL effectively augmented the proliferation of T cells and reduced the number of regulatory T cell (Tregs).When administered to melanoma (B16F10) tumor-bearing mice orally, Roxyl-WL significantly suppressed tumor growth and induced immune response.

【 授权许可】

CC BY